Econazole composition and methods of treatment therewith

ABSTRACT

The invention provides a water-based composition for treating an infection by a dermatophyte fungus comprising econazole or a pharmaceutically acceptable salt thereof. Also provided are methods of treatment utilizing the water-based foam composition, as well as its preparation.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.61/406,826, filed on Oct. 26, 2010, the content of which is incorporatedherein by reference in its entirety.

BACKGROUND OF THE INVENTION

The present invention relates to a water-based composition of siliconeoil, fatty acid(s), and humectant(s), which can be used to treat fungaldiseases, such as tinea pedis, tinea cruris, tinea corporis, cutaneouscandidiasis, tinea versicolor, and the like

A foamable composition similar to the vehicle compositions describedherein is described in U.S. Pat. No. 5,993,830. The composition has beenused with subjects having toxic hand eczema. What was not described, andwhat has now been unexpectedly discovered, is that such compositions canaccelerate healing of wounds and control inflammation. This vehicleeffectiveness is described herein, and in an application filedconcurrently herewith entitled “Composition and Method for TreatingWounds” U.S. Provisional Application No. 61/406,864, filed on Oct. 26,2010.

Econazole nitrate (EN) is representative of azole antifungals. Econazolenitrate is a topical antifungal agent that is currently indicated for avariety of fungal diseases, including tinea pedis, tinea cruris, tineacorporis, and cutaneous candidiasis, as well as for the treatment oftinea versicolor. Econazole nitrate has shown activity against a varietyof dermatophytes and yeasts, including most strains of Epidermophytonfloccosum, Microsporum audouinii, M. canis, M. gypseum, Trichophytonmentagrophytes, T. rubrum, T. tonsurans, Candida albicans, andMalassezia furfur. Econazole nitrate is a leading antifungal usedtopically in the United States, with over 20 years of clinical use andhistory with an excellent safety profile.

Because the vehicle used in the invention is effective in promotingwound healing, it is believed that the composition further containingeconazole will be particularly effective in treating fungal/yeastinfections, and promoting the healing of infection-induced or associatedinjury.

SUMMARY OF THE INVENTION

Provided, in one embodiment, is a method of treating an infection bydermatophyte fungus or a candida yeast comprising: periodically applyingto the infection over a course of days a water-based formulation(comprising: 0.5 to 5 wt % of an emollient comprising silicone oil, 2 to10 wt % of fatty acid, humectant(s), emulsifying agent(s), polymer(s),and a pharmaceutically effective amount of an azole antifungal or aphysiologically acceptable salt thereof), wherein the formulation isformulated as a cream, lotion, milk or foam-former.

Also provided is a method of treating tinea pedis, tinea cruris, tineacorporis, tinea versicolor or cutaneous candidiasis comprising:periodically applying to the infection over a course of days awater-based formulation (comprising: 0.5 to 5 wt % of an emollientcomprising silicone oil, 2 to 10 wt % of fatty acid, humectant(s),emulsifying agent(s), polymer(s), and a pharmaceutically effectiveamount of an azole or a physiologically acceptable salt thereof),wherein the formulation is formulated as a cream, lotion, milk orfoam-former.

Further provided is a composition for treating an infection bydermatophyte fungus or a candida yeast comprising a water-basedformulation (comprising: 0.5 to 5 wt % of an emollient comprisingsilicone oil, 2 to 10 wt % of fatty acid, humectant(s), emulsifyingagent(s), polymer(s), and a pharmaceutically effective amount of anazole or a physiologically acceptable salt thereof), wherein theformulation is formulated as a cream, lotion, milk or foam-former.

Additionally provided is a method of reducing the risk of infection froma skin or mucosa piercing procedure comprising: applying to the skin ormucosa to be pierced an effective amount of a water based formulation(comprising: 0.5 to 5 wt % of an emollient comprising silicone oil, 2 to10 wt % of fatty acid, humectant(s), emulsifying agent(s), polymer(s),and a pharmaceutically effective amount of an azole or a physiologicallyacceptable salt thereof), wherein the formulation is formulated as aspray, cream, lotion, milk or foam-former; and piercing the skin ormucosa.

DETAILED DESCRIPTION OF THE INVENTION

The azole antifungals include, for example the imidazole, triazoles andthiazole antifungals. The imidazole antifungals include, for example,Miconazole, Ketoconazole, Clotrimazole, Econazole, Bifonazole,Butoconazole. Fenticonazole, Isoconazole, Oxiconazole, Sertaconazole,Sulconazole and Tioconazole. The triazoles anfungals include, forexample, Fluconazole, Itraconazole, Isavuconazole, Ravuconazole,Posaconazole, Voriconazole and Terconazole. The thiazole anfungalsinclude, for example, Abafungin. Many if not most of these antifungalsmay be conveniently used as acid addition salts or other salt forms. Anumber of these antifungals share the following structuralcommonalities: a chiral carbon to which is directly linked an aromaticring that has one or more electron withdrawing groups (such as 2 suchgroups, which can for example be fluoro or chloro); and one or moreazole groups linked to the chiral carbon by a methylene bridge. Theazole groups can be linked to the methylene a ring nitrogen of the azolering.

Azole antifungal drugs are believed to inhibit the P-450 class enzyme14α-demethylase; the enzyme that converts lanosterol to ergosterol.Depletion of ergosterol in fungal membranes is believed to disrupt thefungal membrane. It should be recognized that while typically a singleazole compound will be used, mixtures can also be used. References in“an azole” encompass mixtures unless the contrary is specificallyrecited.

In certain embodiments, the formulation of the invention provides anon-irritating composition. Irritation, in certain embodiments, ismeasured by ISO 10993-10: 2002 Standard, “Biological Evaluation ofMedical Devices, Part 10-Tests for Irritation and Sensitization,” pp.6-10, 21, which testing method is incorporated herein by reference. Inparticular, for each test site on shaved dorsal skin of an albinorabbit, gauze incorporating 0.5 mL of test material or negative controlmaterial is applied. One test and one control site are used on each sideof the paravertebral skin. The infused gauzes are covered withtape-backed gauze. The trunk of the rabbit is wrapped in elastic bandagesecured by hypoallergenic tape. After a minimum of 24 hours, thecoverings are unwrapped. Observations are made at 60 min+2, 24 h+2, 48h+2 and 72 h+2 post unwrapping. Tissue reactions are rated for grossevidence of erythema and edema.

For a given rabbit, values for each test site and each of the 24 h, 48 hand 72 h measurements are totaled, and divided by six (2 tests sites×3measurements). Control values were treated in the same way. For allrabbits, these test values were summed, normalized against the summedvalues for the negative controls, and divided by the number of animals.A negligible, slight, moderate or severe response is categorized basedon the Primary Irritation Index:

Response Category Comparative Mean Score Negligible   0 to 0.4 Slight0.5 to 1.9 Moderate   2 to 4.9 Severe 5 to 8

By “non-irritating” it is meant that compositions according to thisembodiment of the invention illicit a Negligible Primary IrritationIndex.

The non-irritating quality of these embodiments is surprising in view ofthe surfactants often found in these embodiments. While not being boundby theory, it is believed that water and appropriate selection ofrelatively mild surfactants, as illustrated herein, may contribute tothe non-irritating quality of the composition.

Irritation, in certain embodiments, is measured by the 21-Day CumulativeIrritation procedure, originally introduced by Lanman et al. (JointConference on Cosmetic Sciences, the Toilet Goods Association (now namedThe Cosmetic, Toiletry and Fragrances Association) Wash. D.C., Apr.21-23, 1968), that has been successfully employed as a test forcomparing the irritation potential of mild to moderately irritatingtopically applied skin care products. The procedure involves dailyconsecutive applications of occlusive patches to human skin over a21-Day period. Each of the patches applied is worn for approximately 24hours, removed under supervision and the sites scored by a trainedevaluator.

The relative cumulative irritation potential of topically applied testarticles can be compared to a negative (Johnson's® Baby Oil) and apositive (0.2% v/v sodium lauryl sulfate) control following repetitivedaily applications to the skin of normal healthy, adult volunteers. Thetest articles, in addition to Johnson's® Baby Oil and 0.2% Sodium LaurylSulfate (v/v in DI water) are rubbed in to the upper back between theleft and right infra-scapular areas and then covered with a blanksemi-occlusive patch. Test article application sites are randomized tolimit site bias. Products are rubbed in and blank semi-occlusive patcheswere applied to the same sites every day for twenty-one (21) consecutivedays for a total of 21 applications. Each patch is worn forapproximately 24 hours, removed under clinical supervision and the testsites evaluated approximately 10 minutes following patch removal. If adermal reaction of a 3-level or greater occurs with any of the testarticles at any point during the study, further patch testing on thatsubject at the test site involved is terminated and the observed scoreis assigned to that site for all remaining scheduled test days (i.e.,last score observed carried forward). If a test site is discontinued forreasons other than a dermal reaction of a 3-level or greater (due toerosion, scabbing, etc.), an erythema score of 3 and any other alphacharacter associated with the score is imputed and assigned to that sitefor all remaining scheduled test days. If a test subject exhibits asignificant degree of irritation to the adhesive such that patchreapplication is not feasible, the test subject is discontinued from thestudy and the scores for this subject were not used in determining thecumulative irritation totals. When warranted, individual sites arediscontinued due to tape reaction (i.e., tape dermatitis) and are notused in determining the cumulative irritation totals. Individual testarticle scores are calculated via summation of the results for each day.Subjects receive 21 rub-in applications of 0.2 mL of the test articles(including controls) to both sides of their back during the course ofthe study. Total cumulative irritation scores are determined for eachtest article by summing the daily erythema scores for each subject.

In certain embodiments, the composition of the invention has a“non-greasy feel” when applied. A non-greasy feel is measured inreference to a comparison of the feel of the Example 1 composition(non-greasy standard) of U.S. application Ser. No. 12/016,371, filedJan. 18, 2008 (U.S. 2008/175793), applied to skin at 1 mg/cm², comparedto the oil-based product described in the Table at Column 3 of U.S. Pat.No. 5,919,470 (Bradley Pharmaceuticals, Inc., greasy standard), appliedin the same amount. Application includes working the composition intothe skin. While the feel of compositions of the invention may vary, inmaking the comparison between the non-greasy standard, the greasystandard, and the prospective non-greasy composition, it will beapparent which category the prospective composition falls within. Thenon-greasy skin feel may be moist and smooth feeling, but the differencein greasy feel relative to the greasy comparative shall be clear.

In certain embodiments, the composition of the invention has a“non-watery feel” when applied. A non-watery feel is a feel much likethat of the Example 1 composition (non-watery standard) of U.S.application Ser. No. 12/016,371, filed Jan. 18, 2008 (U.S. 2008/175793),applied to skin at 1 mg/cm². A feel that, in contrast, is noticeablymore watery, is disqualified.

In certain embodiments, the formulation of the invention provides anon-sensitizing composition. Sensitization, in certain embodiments, ismeasured by ISO 10993-10: 2002 Standard, “Biological Evaluation ofMedical Devices, Part 10-Tests for Irritation and Sensitization,” pp.6-10, 21, which testing method is incorporated herein by reference.Dermal sensitization testing for topical products places into differentcategories based on their potential to cause dermal sensitization inguinea pigs and extrapolating the results to humans.

In the Induction Phase, ten test guinea pigs are patched with acomposition of the invention and 5 guinea pigs are patched with thenegative control article, removed after at least 6 hour exposure. Aftera 24-hour rest period, each site was observed for erythema and edema.The procedure is repeated 3 times per week for 3 weeks. In the ChallengePhase, following a 2 week rest period, the animals are topically patchedagain, removed after at least 6 hours of exposure. Dermal patch sitesare observed for erythema and edema 24 and 48 hours after patch removal.Each animal is assessed for a sensitization response and test resultswere based upon incidence and severity of the sensitization reaction.

Certain embodiments involve the treatment of “partial thickness wounds,”which for the purposes of this application are those that involve theepidermis and at least a portion of the dermis. Wound healing ismeasured in the pig model by International Standards Organization (ISO)Guidelines 10993-1 (2003), 10993-2 (2006), 10993-4 (2002), and/or10993-6 (2007). This kind of study is conducted to determine the effectscompositions of the invention applied topically on wound healing in asplit thickness skin graft model in the pig. Domestic Yorkshirecrossbred swine undergo a single surgical procedure during which sixsplit thickness skin graft wounds were created using a dermatome on thedorsum, three wounds on either side of the dorsal midline. Each site istreated with one of three treatments, Standard Care Dressing(non-adherent absorbable dressing, Johnson & Johnson), Positive Control1 (Biafine Ointment), or the Test Article (ProDerm—Hydrometic Foam). Thetopical treatments are applied topically to wound sites once daily for14 days at a dose volume of approximately 4 mg/cm² (approximately 25mg). Observations for morbidity, mortality, injury, and the availabilityof food and water are conducted, for example, twice daily. Clinicalobservations are for example conducted weekly. Body weights are measuredand recorded pretest and (for example) weekly. Physical examinations areconducted pretest. Blood samples for clinical pathology evaluations arecollected from all animals pretest. Wound sites of all animals areevaluated for healing and photographs were obtained from all animals onDays 1 (evaluation only), 4, 7, 10 and 14. Wound measurements areperformed in the wound area for all animals on Days 4, 7, 10, and 14. Atstudy termination, complete necropsy examinations are performed andselected tissues were microscopically examined.

References to the vehicle formulation being effective in wound healingrefer to effectiveness in the pig model as outlined in thisspecification.

In certain embodiments, the formulation of the invention isnon-comedogenic where the method of measuring comedogenicity is amodification of that described by Dr. Otto Mills (Mills et al., Archivesof Dermatology 118: 903-905, 1982). For example, one of the compositionsof Table A (described below) was tested using this model. Testing canbe, for example, in a single center, test site randomized studycomparing the ability of the composition to induce microcomedoneformation relative to a positive (Acetulan™) and a negative (BlankPatch) control. Approximately 0.2 mL of the composition and the positivecontrol are applied to blank semi-occlusive patches (TruMed™ patchescontaining needle punch absorbent cotton and Alpharma Scantape, BradyMedical, Mesquite, Tex.) and these patches, along with a negativecontrol (blank semi-occlusive patch), are applied to the upper backbetween the left and right infra-scapular areas. Patch application sitesare randomized as to their position on the subjects' backs to eliminatetest site bias. Patches are applied three times a week (e.g., everyMonday, Wednesday and Friday) for twelve patch applications (i.e., 4weeks) to the designated test sites. Subjects are instructed to wear thepatches continuously for 48 hours following the first and second weeklypatch applications and continuously for 72 hours after the third patchapplication. The sites were scored for the presence of erythemaaccording to an agreed upon scale.

At the final visit, after all patches are removed and the test sites arescored for erythema, follicular biopsies of the sites were collectedusing a cyanoacrylate follicular biopsy technique. Follicular biopsiesare examined under a stereo microscope and the number of microcomedonespresent on the slides counted. The number of microcomedones present atthe treated test sites are compared to that observed for the positiveand negative control sites to determine significance. The negativecontrol should significantly less microcomedones than the positivecontrol to a high statistical confidence (e.g., P≤0.05). Where thenumber of microcomedones at the sites treated with the test compositionare not significantly different from the number of microcomedonesobserved at the negative control sites, the test composition is“non-comedogenic.”

In certain embodiments, the formulation vehicle is effective treatingsplit thickness graft wounds. The “vehicle” will be recognized by thoseof skill—it is composed of the components of the composition less theazole or azole salt, and any titrant added to form an azole salt.

To treat the wound indications of the invention, an “effective amount”of the composition will be recognized by clinicians but for woundsincludes an amount effective to accelerate healing to a degreecomparable to Biafine Ointment. In certain embodiments for treatingwounds, the effective amount is effective to accelerate healing to adegree superior to Biafine Ointment. To treat the fungal oryeast-infection associated indications of the invention, an “effectiveamount” of the composition will be recognized by clinicians but includesan amount effective to treat, reduce, alleviate, ameliorate, eliminateor prevent one or more symptoms of the disease sought to be treated orthe condition sought to be avoided or treated, or to otherwise produce aclinically recognizable favorable change in the pathology of the diseaseor condition.

Generally, the formulation of the invention is applied two to threetimes a day to the affected tissue, in amounts of 1 to 5 mg/cm², or asneeded or prescribed. Where used to treat an oozing indication, thetreatment site can be dabbed with sterile gauze or the like prior toapplication.

For certain indications, the foam or gel form may often be selected dueto the greater ease in assuring coverage of the affected tissue.

In certain embodiments using the foam form, the foam is a stable foam,meaning that when applied to the skin at one of 1, 2 or 3 mg/cm² and notworked into the skin, the foam remains a stably adherent foam for 30seconds or more. In some cases, the foam remains a stably adherent foamfor 60 seconds or more, 120 seconds or more, 150 seconds or more or 180seconds or more. Though stable, the foam can be worked into thepatient's skin.

In certain embodiments, the composition of the invention is essentiallyfree of C1 to C6 alcohols (but not including polyols, such as glycerinor propylene glycol). In certain embodiments, the composition isessentially free of C1 to C5 alcohols (but not including polyols, suchas glycerin or propylene glycol). In certain embodiments, thecomposition is essentially free of C1 to C4 alcohols (but not includingpolyols, such as glycerin or propylene glycol). By essentially free itis meant that such alcohols may be present in minor amounts, as may beuseful for example for compounding, but are not present in an amountthat one of skill in the art of pharmaceutical composition formulatingwould select to stabilize components of the composition. In theseembodiments, the amount of such alcohols is less than about 8 wt %. Incertain embodiments, the amount of such alcohols is less than about 5%,or 2%, or 1%, or 0.5%, or 0.25% (wt/wt).

When worked into the skin, the compositions of the invention can haverapid absorption—contributing to their non-greasy and non-watery feels.The compositions can be easy to spread and are cosmetically elegant.

While the compositions can contain active ingredients, such asantimicrobial agents, surprisingly the wound treating efficacy can beobtained without such agents, using only components that are nottraditionally regarded as active ingredients. While not being bound bytheory, it is believed that this efficacy is due to (a) physicallyproviding a protective artificial barrier on the affected surface; (b)providing moisture to the skin/mucosa and improving its hydration; and(c) effectively controlling the inflammation in the affected area.

The vehicle is formulated with an azole. The azole can be the racemate,or it be enriched in one or the other stereoisomer. Liao et al., Yao XueXue Bao 28 (1):22-7 (1993), report that the (R)-(−)-econazole hasgreater antifungal activity. Aboul-Enein et al., Chromatographia54:200-202 (2001), report that the racemate can be resolved on by chiralchromatography. The current invention can be used with sterio-enrichedisomer. Azole can be formulated as the acid addition salt. The nitrateis can be used, as cab any pharmaceutically acceptable salt. Doseconcentration in the formulation will typically be about 0.5% w/w toabout 1.5% w/w, such as about 1%.

The composition contains fatty acids, which can be substantially oressentially ionized, wherein the salt may be more soluble or suspendablein the aqueous solvent of the composition. The fatty acids are, incertain embodiments, non-greasy, meaning that in the aggregate of theformulation, as formulated in the composition, they are non-greasy.

The fatty acid can, for example, be of any composition found in anatural source, including hydrolysis of esterified fatty acids. Or, thefatty acid component can be hydrogenated to remove substantially all ora portion of any unsaturation. In certain embodiments, the fatty acidcomponent is selected such that 50 mole % or more is C12 or higher, orC14, or C16 or higher. In certain embodiments, the fatty acid componentis selected such that 50 mole % or more is C22 or lower, or C20 orlower, or C18 or lower. In certain embodiments, 75 mole % or more of thefatty acid component is from C12 or C14 or C16 to C22 or C20 or C18. Incertain embodiments, 80 mole % or more, 85 mole % or more, 90 mole % ormore, 95 mole % or more, 97 mole % or more, 98 mole % or more, or 99mole % or more, meets one of the size parameters of this paragraph.

Useful salts of the fatty acids include the alkali metal salts such assodium or potassium salts; ammonium salts; salts formed with suitableorganic bases, such as amine salts (such as triethyl amine, triethanolamine, or the like) and quaternary ammonium salts; or the like. Bivalentor trivalent salts can be used where they do not adversely affectsolubility. As needed, the fatty acid components are provided such thata sufficient amount of constituent ionizable molecules are in ionized(salt) form to provide solubility. Such ionized forms can be prepared byadding a titrant. Recitations of compositions described by theirformation by titration include the equivalent compositions formed bypre-formed salts or otherwise.

In certain embodiments, the fatty acid(s) comprise an amount of E ormore, F or less, of from E to F of the composition, where E is 2, 2.1,2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6,3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1,5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 or 6 wt %, and F is 2.1, 2.2,2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7,3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2,5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7,6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8. 8.1, 8.2,8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7,9.8, 9.9 or 10 wt %. Unless otherwise specified, the compositionpercentages for the compositions are exclusive of any propellant, suchas propane or butane or the like.

An emollient, if present, can be a silicone oil such aspolydimethylsiloxane (i.e., dimethicone), petrolatum (natural orsynthetic), or the like. In certain embodiments, the emollient(s) are anamount I or more, J or less, or I to J of the composition, where I is0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9,2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4,3.5, 3.6, 3.7, 3.8, 3.9 or 4 wt %, and J is 0.6, 0.7, 0.8, 0.9, 1, 1.1,1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6,2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1,4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 or 5 wt %. In certainembodiments, as among emollients and fatty acids in the composition, theamount of emollient is an amount K or more, L or less, or K to L of theemollients and fatty acids, where K is 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19 or 20 wt %, and L is 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 wt %. Relative amountsof any petrolatum can be selected to minimize comedogenicity. In certainembodiments, silicone oil is a major portion of the emollient componentby weight. In certain embodiments, silicone oil is 80, 85, 90, 95, 96,97, 98, 99, 99.5% or more of the emollient component (by weight).

The composition will typically include emulsifying agents. Emulsifyingagents can be non-ionic detergents, such as polyoxyethylene sorbitanfatty acid esters (such as Tween 80 (polyoxyethylene (20) sorbitanmonolaurate), Polysorbate 20 (polyoxyethylene (20) sorbitanmonooleate)), sorbitol fatty acid esters, octyly glucosides, PEGylatedlipids and the like. In certain embodiments, the emulsifying agent(s)comprise an amount of M or more, N or less, of from M to N of thecomposition, where M is 0.5, 0.6, 0.7, 0.8, 0.9, 2, 1.1, 1.2, 1.3, 1.4,1.5, 1.6, 1.7, 1.8, 1.9 or 2 wt %, and N is 1.1, 1.2, 1.3, 1.4, 1.5,1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3,3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 or 4 wt %. The emulsifyingagent(s) can comprise detergents with 2 or more, 3 or more, 4 or more, 5or more fold difference in CMC. The emulsifying agents can, for example,have a CMC at 21° C. of 2×10⁻⁶M to 10⁻⁴M. In certain embodiments, wherethere are two or more frothing agents, the predominant (by wt) frothingagent can have the lower CMC vs the next most predominant frothingagent.

Hydrophilic polymer(s) can be present. These can be any non-toxic watersoluble polymer(s) that (in the aggregate) stabilize composition andcontribute to film formation on the skin. Examples include polyvinylpyrrolidone, polyethylene glycol, starch, water-soluble derivatives ofstarch, cellulose, methyl cellulose, hydroxymethylcellulose, otherwater-soluble derivatives of cellulose, carbomers, or the like. Forpolyvinyl pyrrolidone, for example, useful average molecular weightsinclude from 8,000 to 63,000, such as about 38,000. For all polymersused in the composition, the size can be sufficient to limit penetrationof the horny layer of the skin, if skin penetration is an issue for thegiven polymer. In certain embodiments, hydrophilic polymer(s) are anamount I or more, J or less, or I to J of the composition.

The composition can also contain a humectant, such as glycerol,propylene glycol, other polyols, polydextrose, lactic acid, or the like.In certain embodiments, humectant(s) are an amount 0 or more, P or less,or O to P of the composition, where O is 4, 4.1, 4.2, 4.3, 4.4, 4.5,4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6,6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5,7.6, 7.7, 7.8, 7.9 or 8 wt %, and P is 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6,5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1,7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6,8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.1,10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11, 11.1, 11.2, 11.3,11.4, 11.5, 11.6, 11.7, 11.8, 11.9 or 12 wt %.

The composition can optionally contain a preservative or preservativesystem but preferably does not. Examples include Phenonip™ XB (a mixtureof preservatives, believed to include phenoxyethanol, methylparaben,ethylparaben, butylparaben, propylparaben and isobutylparaben; fromClariant UK Ltd., Leeds, UK), or a less complex preservative, such asone or two of methylparaben, ethylparaben, butylparaben, propylparaben,isobutylparaben, benzalkonium chloride, imidurea or the like.

The compositions will typically contain titrating agents such astriethylamine, trolamine, NaOH, citrate, phosphates, and the like, withtrolamine being preferred. The amount is typically selected to provide adermatologically or physiologically acceptable pH, such as pH 4-9, or5-9, or 6-9.

The compositions can be formulated as sprays, creams, lotions, milks,foam-formers, and the like. Where creams or lotions are desired, theseconsistencies can be obtained by selection of hydrophilic polymers, andthe amounts thereof. For example, these can include polymers that have agreater effect on increasing viscosity, in appropriate amounts. Suchpolymers can include, for example, appropriate carbomers, carbopols,methylcellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose,hydroxypropyl cellulose, polyvinyl pyrrolidone, hypromellose,polyethylene glycol, polyethylene oxide, xanthan gum, Arabic gum,pectin, starch, alginate, and the like. Addition of suitable hydrophilicco-polymer permits the formation of different forms that retain the samesafety and efficacy properties as the foam-forming formulations but donot require the use of gaseous propellants for their delivery to thetreatment area. In such embodiments, it may be that the amounts ofpolymer are to the high end or greater than those amounts discussedabove.

Suitable propellants include, for example, propane, butane, isobutene,other hydrocarbons, hydrofluorocarbons, chlorofluorocarbons(Cl/F/(H)/C), and the like. Dispensing devices include those availablefrom Deutsche Prazision, Lindal Group (Schonberg, Germany), Coster(Milano, Italy) and SeaquistPerfect Dispensing (Cary, Ill.).

The formulation of the invention is, in certain embodiments, a stableemulsion. In others, the formulation provides an emulsion whenshaken/agitated prior to use. For certain of the foam embodiments, theformulation should be shaken/agitated prior to use. Applicants havefound that two-phase emulsions which are shaken/agitated prior to useprovides good distribution of propellant and drug. Certain foamembodiments provide a foam that is relatively stable at 35° C., such asstable for 1 or more minutes, or 2 or more minutes, or 3 or moreminutes, a period of time allowing for convenient transfer of the foamfrom a gloved or naked hand to the tissue to be treated. In certainembodiments, including certain thermally stable embodiments, the foambreaks, i.e., loses its foam texture, on application of the shear usedto manually apply the foam to the tissue.

Vehicle formulations of the invention have been found to be remarkablyantimicrobial. As such, they can be used prepare skin or mucosa fortreatments that are skin or mucosa piercing, such as surgery, IVs,needle biopsies, acupuncture, and the like. Mucosal tissues that arecandidates for treatment include, for example, esophageal mucosa, rectalmucosa, anal mucosa, urethral mucosa, vaginal mucosa, external mucosa,oral mucosa, and the like. Furthermore, the antimicrobial nature of thevehicle means that formulations can be prepared which lack preservativesor preservative systems.

For example, forearm areas were treated with vehicle formulation for 5,10, 20 or 40 minutes, then challenged with ˜10⁵ CFU of Escherichia coli(ATCC #11229) or Staphylococcus aureus aureus MRSA (ATCC #33593).Microbial colonization was inhibited to a statistically significantextent after 10 minutes exposure or more for Staph. aureus MRSA, andafter 20 minutes or more for E. coli.

One can test antimicrobial effect in an in vitro time kill method, suchas by mixing 0.1 mL challenge bacterial suspension with 9.9 g of testproduct. After one minute, 1.0 mL of the mix is 9.0 mL of Butterfield'sPhosphate Buffer with neutralizers. Serial dilutions into the samebuffer are plated onto Tryptic Soy agar plates.

Periodic application of the composition can be used to treat infectionsby dermatophyte fungus or a candida yeast. Periodic application of thecomposition can be used to treat tinea pedis (moccasin and/orinterdigital), tinea cruris, tinea corporis, tinea versicolor orcutaneous candidiasis. Periodic application of the composition can beused to treat topical infections of Epidermophyton floccosum,Microsporum audouinii, M. canis, M. gypseum, Trichophytonmentagrophytes, T. rubrum, T. tonsurans, Candida albicans, or Malasseziafurfur.

In certain embodiments, the compositions used in the methods of theinvention lack any antimicrobial compounds other than azole antifungal,where the emollient, fatty acid, humectant and emulsifying agents arepresent in amounts appropriate to provide skin moisturization, skinbarrier repair (fatty acid), and the texture properties desired (spray,cream, and the like). In certain embodiments, the emollient, fatty acid,humectant and emulsifying agents are present in amounts appropriate toprovide one or more of non-irritation, non-sensitization ornon-comedogenicity. In certain embodiments, the emulsifying agentconsists essential of (no other present in amounts beyond minor amountssuch as 0.1% by wt used to facilitate making intermediate formulationsused in the formulation process) nonionic detergent(s). The nonionicdetergents can be those where polyoxyethylene and or sugar moietiesprovide the hydrophilic portion, and hydrocarbons (e.g., alkanyl oralkenyl) provide the hydrophobic portion.

To formulate 100 g, one can formulate all or a selection of theformulations defined by the combinations of the following options:

TABLE A Component Amt. Options (g) A Stearic acid 2.0-8.0 A PVP 1.0-5.0B Azole salt 0.5-1.5 A Propylene glycol 4.0-8.0 A Glycerin 1.0-5.0 ADimethicone 0.5-5.0 A Triethanolamine 2.0-3.0 A Polysorbate 20 1.0-4.0Water Quantity Sufficient

The above can be formulated by mixing the A components stepwise withwater heated to promote mixing and solubilization. The B component isadded to the A components at a temperature allowing for the fatty acidto mainly be in a melted configuration. A fine dispersion is obtained byusage of a mixer/homogenizer and temperature is brought down to ambient.The formulations can be tested for active content, foam forming (ifappropriate), foam stability (if appropriate), non-wet feel, irritation,non-greasy feel, and the like.

In a preferred embodiment, the azole salt is first mixed with theemulsifying agent, e.g., Polysorbate 20, to create an API slurry phase,which is then added to the remaining ingredients except for thetitrating agent, e.g., trolamine. The trolamine is then added and themixture maintained at the proper temperature (e.g., about 50-55° C.)until visually uniform. The mixture can then be cooled (e.g., about28-32° C.).

Specific embodiments according the present invention will now bedescribed in the following examples. The examples are illustrative only,and are not intended to limit the remainder of the disclosure in anyway.

EXAMPLES Example 1: Wound Care

The vehicle for one of the compositions of Table A was tested in a woundtreatment model. This composition is designated Test Article in the textbelow.

Animal Care

Experimentally naive female Domestic Yorkshire crossbred swine, at least9 weeks of age at receipt, were used. The animals were originallyreceived from Whiteshire Hamroc, Albion, Ind. Prior to use in the study,the animals were weighed weekly and observed with respect to generalhealth and any signs of disease. Ova and parasite evaluations on stoolsamples were performed, and all results were negative for animals placedin the study.

The animals were individually housed in runs with raised flooring. Thistype of housing provided adequate room for exercise for these animals.Fluorescent lighting was provided for approximately 12 hours per day.Temperature and humidity were continuously monitored and recorded. Theprotocol-designated ranges were 61 to 81° F. and 30 to 70%,respectively. Diet (Certified Lab Diet® #5K99, PMI NutritionInternational, Inc.) was offered via limited feedings, except duringdesignated periods. Tap water was available ad libitum via an automaticwatering system.

Wounding Procedure

The animals were fasted overnight prior to surgery and treated asspecified in Table C. Prior to surgery, the appropriate drugs wereadministered and general anesthesia was induced. A cuffed endotrachealtube was placed and general anesthesia was maintained with isofluranedelivered in oxygen through a rebreathing system with ventilator assist.

TABLE C Procedure-related Medications and Dose Levels Interval, DoseLevel, and Route Medication Surgery (Day 0) Daily PostsurgeryAcepromazine malease 0.1 mg/kg IM — Atropine sulfate 0.05 mg/kg IM —Telazol 5 mg/kg IM — Isoflurane To effect, inhalation — Buprenorphine0.02 mg/kg IM 0.01 mg/kg IM TID × 3 days Cefazolin 25 mg/kg IV —Ceftiofur 2.2 mg/kg IM  2.2 mg/kg IM SID × 5 days Lactated Ringer's 5 to6 mL/kg/hour IV — Solotion (LRS) IM—Intramuscular IV—IntavenousTID—Three times daily SID—Once daily

All surgical procedures were performed utilizing routine aseptictechnique. Following induction of anesthesia, the entire dorsal surfacewas prepared for surgery with Iodine Scrub, 70% isopropyl alcohol, andIodine solution.

Following completion of preoperative procedures on Day 0, six 2.5 cm×2.5cm wound sites were marked out, three on either side of the dorsalmidline caudal to the scapula and 2.5 cm (animal numbers 101 and 102) or5 cm (animal numbers 103 and 104) from the midline, using sterile skinmarker pens. The wounds were separated from each other (approximately 5cm) to avoid wound to wound contact. To avoid cross-contamination ofTest Article treated wounds with wound treated by Positive ControlArticle (Biafine Ointment, OrthoNeutrogena) [purified water, liquidparaffin, glycol monostearate, stearic acid, propylene glycol, paraffinwax, squalene, avocado oil, trolamine sodium alginate, cetyl palmitate,methylparaben, sorbic acid, propyl paraben and fragrance] and StandardCare (non-adherent absorbable dressing, Johnson & Johnson), the StandardCare wound sites were wounded first, followed by the Positive ControlArticle wounds and then Test Article. The skin covering the wound siteand the dermatome was moistened with sterile saline using sterile gauzeimmediately prior to each wound to aid the running of the dermatome. Six2.5 cm×2.5 cm×0.50 mm (length×width×depth) split thickness skin graftwounds were created using the dermatome; three wounds were created oneach side of the dorsal midline.

If necessary, a pair of scissors was used to aid in the removal of skin.The portion of the dermatome in contact with the skin was frequentlycleaned with chlorhexadine, and then rinsed with sterile saline. Thedermatome blade was changed following completion of the wounding in eachpig, prior to commencement of wounding the subsequent pig. Following thecompletion of wounding, a piece of dry sterile gauze was placed on eachwound to absorb excess blood. Following removal of the sterile gauze theappropriate treatment was applied to the wound. The Positive Control andTest Article were applied to each designated wound site by spreadingevenly with a sterile spatula (dose volume of approximately 4 mg/cm², 25mg). A piece of non-adherent absorbable dressing (Johnson & Johnson) wasplaced on each wound. The non-stick dressings on each side of the pigwere held in place using a sheet of Bioclusive transparent dressing(Johnson & Johnson). The Bioclusive was carefully placed on the wounds,ensuring that it was not pulled too taught to avoid skin irritation.Care was taken to seal the Bioclusive dressing around the four edges ofeach non-stick dressing. Following the placement of the Bioclusivedressing, the wounds were dressed with Elastikon® elastic tape (Johnson& Johnson). A Surgilast (Glenwood, Inc., Tenafly, N.J.) equivalent toSurgifix (FRA Production S.p.A., Cisterna D'Asti, Italy) stocking wasplaced on the body of the animal.

Monitoring was conducted during anesthetic recovery for physiologicaldisturbances including cardiovascular/respiratory depression,hypothermia, and excessive bleeding from the surgical site. Theendotracheal tube was removed after the animal regained the swallowreflex. Long-term postoperative monitoring included daily inspection ofsurgical sites. Medications were administered as presented in Table C.

Wound Administrations

The treatments, Standard Care Dressing (sterile gauze bandage), PositiveControl, and Test Article, were administered via topical application tosix split thickness skin graft wounds created on the dorsum of the pig.Treatments were administered once daily for 14 days at a dose volume ofapproximately 4 mg/cm² (approximately 25 mg). Wounds were randomlytreated with each of the three treatments in a manner that allowed eachanimal to receive two sites treated with each treatment.

On each day of the study (Days 1 to 14), Telazol (5 to 6 mg/kg, IM) wasadministered and anesthesia was maintained with isoflurane delivered inoxygen. The bandages were then removed. For the Standard Care treatedwounds, the Surgifix stocking or equivalent and Elastikon® elastic tapewere removed. The Bioclusive transparent dressing and non-adherentabsorbable dressing was then removed from the wound. The site wascarefully cleaned with sterile saline and gauze. Following cleaning, apiece of non-adherent absorbable dressing was placed on each wound. Thenon-stick dressings on each side of the pig were held in place using asheet of Bioclusive transparent dressing. The Bioclusive was carefullyplaced on the wounds, ensuring that it was not pulled too taught toavoid skin irritation. Care was taken to seal the Bioclusive dressingaround the four edges of each non-stick dressing. Following theplacement of the Bioclusive dressing, the wounds were dressed withElastikon® elastic tape. A Surgifix stocking or equivalent was placed onthe body of the animal.

For the Positive Control treated wounds, the Surgifix stocking orequivalent and Elastikon® elastic tape was removed. The Bioclusivetransparent dressing and non-adherent absorbable dressing was thenremoved from the wound. The site was carefully cleaned with sterilesaline and gauze to remove any residual material. Following cleaning,the site was dosed and a piece of non-adherent absorbable dressing wasplaced on each wound. The non-stick dressings on each side of the pigwere held in place using a sheet of Bioclusive transparent dressing. TheBioclusive was carefully placed on the wounds, ensuring that it was notpulled too taught to avoid skin irritation. Care was taken to seal theBioclusive dressing around the four edges of each non-stick dressing.Following the placement of the Bioclusive dressing, the wounds weredressed with Elastikon® elastic tape. A Surgifix stocking or equivalentwas placed on the body of the animal.

For the Test Article treated wounds, the Surgifix stocking or equivalentand Elastikon® elastic tape was removed. The Bioclusive transparentdressing and non-adherent absorbable dressing was then removed from thewound. The site was carefully cleaned with sterile saline and gauze toremove any residual material. Following cleaning, the site was dosed anda piece of non-adherent absorbable dressing was placed on each wound.The non-stick dressings on each side of the pig were held in place usinga sheet of Bioclusive transparent dressing. The Bioclusive was carefullyplaced on the wounds, ensuring that it was not pulled too taught toavoid skin irritation. Care was taken to seal the Bioclusive dressingaround the four edges of each non-stick dressing. Following theplacement of the Bioclusive dressing, the wounds were dressed withElastikon® elastic tape. A Surgifix stocking or equivalent was placed onthe body of the animal.

Erythema and Edema

The wound and skin around the wound was assessed for the presence oferythema and edema. Assessment of erythema and edema was made after thewound had been gently cleaned, if needed, ensuring no damage was caused.Assessment of erythema and edema was graded on the following 5 pointscales, according to Draize (Draize J H, Woodard G, Calvery H O. Methodsfor the study of irritation and toxicity of substances applied topicallyto the skin and mucous membranes. J Pharmacol Exp Ther 1944; 82:377-390,1959) 4 point acute dermal irritation scale.

TABLE F Erythema Formation Score Observation 0 No erythema 1 Very slighterythema (barely perceptible) 2 Well-defined erythema 3 Moderate tosevere erythema 4 Severe erythema (beet redness) to eschar formation(injuries in depth) Maximum possible score = 4

TABLE G Edema Formation Score Observation 0 No edema 1 Very slight edema(barely perceptible) 2 Slight edema (edges of area well-defined bydefinite raising) 3 Moderate edema (raised approximately 1 mm) 4 Severeedema (raised more than 1 mm and extending beyond area of exposure)Maximum possible score = 4

Results were:

TABLE J Individual Wound Healing Scores: Erythema Study Standard CarePositive Interval Dressing Control 1 Test Article (Days) Score (n = 8)(n = 8) (n = 8) 1 0 - no erythema 8 7 8 1 - very slight 0 1 0 2 - welldefined 0 0 0 4 0 - no erythema 6 5 6 1 - very slight 2 3 1 2 - welldefined 0 0 1 7 0 - no erythema 4 7 7 1 - very slight 4 1 1 2 - welldefined 0 0 0 10 0 - no erythema 5 5 7 1 - very slight 3 3 1 2 - welldefined 0 0 0 14 0 - no erythema 4 5 7 1 - very slight 4 3 1 2 - welldefined 0 0 0 No sites were scored greater than 2 and as such the datais not presented in the summary table.

TABLE K Individual Wound Healing Scores: Edema Study Standard CarePositive Interval Dressing Control 1 Test Article (Days) Score (n = 8)(n = 8) (n = 8) 1 0 - no edema 8 8 8 1 - very slight 0 0 0 4 0 - noedema 7 6 5 1 - very slight 1 2 3 7 0 - no edema 6 8 8 1 - very slight 20 0 10 0 - no edema 8 8 8 1 - very slight 0 0 0 14 0 - no edema 8 8 81 - very slight 0 0 0 No sites were scored greater than 1 and as suchthe data is not presented in the summary table.

Exudate

The wound and skin around the wound was assessed for the presence ofexudate. Assessment of exudate was made after the wound had been gentlycleaned, if needed, ensuring no damage was caused to the wound in doingso. Assessments were graded according to the following 5 point scale.The results were:

TABLE L Individual Wound Healing Scores: Exudate Study Standard CarePositive Interval Dressing Control 1 Test Article (Days) Score (n = 8)(n = 8) (n = 8) 1 0 - none 0 0 0 1 - mild 0 1 1 2 - moderate 7 7 7 3 -severe 1 0 0 4 0 - none 0 0 0 1 - mild 2 2 2 2 - moderate 6 6 5 3 -severe 0 0 1 7 0 - none 4 7 8 1 - mild 4 1 0 2 - moderate 0 0 0 3 -severe 0 0 0 10 0 - none 8 8 8 1 - mild 0 0 0 2 - moderate 0 0 0 3 -severe 0 0 0 14 0 - none 8 8 8 1 - mild 0 0 0 2 - moderate 0 0 0 3 -severe 0 0 0 No sites were scored greater than 3 and as such the data isnot presented in the summary table.

Wound Size

Digital photographs of the site of surgery were taken on Days 4, 7, 10,and 14 during dressing changes and prior to necropsy. Photographs weretaken after dressings had been removed and the wound had been gentlycleaned, if needed, ensuring no damage was cause to the wound in doingso. For all photographs, a measurement scale was place in the same planeas the surgical sites. Morphometry was performed in the wound area todocument changes in wound size. Morphometry was used to determineadvancement of wound edge, reduction in total area/percent closure, andtime to complete healing.

On Days 4, 7, 10, and 14, digital photos were taken of each wound andthe wound area was measured by tracing the edge of the wound. When thewound was considered to be completely healed, the area measurement was0. The results were:

TABLE M Average Wound Area (mm²) Time point Treatment Day 4 Day 7 Day 10Day 14 Standard Care Mean Area 590.1 177.6 115.5 0.0 SD 39.93 232.11135.17 0.00 Positive Control Mean Area 616.4 44.3 87.7 0.0 SD 45.48101.97 165.58 0.00 Te.st Article Mean Area 632.2 18.8 0.0 0.0 SD 57.0039.00 0.00 0.00

The results of this study demonstrate that application of the TestArticle (a cream according to the invention) daily to a split thicknessskin graft wound in the pig does not adversely affect wound healing.Application of the Test Article was found to reduce the incidence oflocalized erythema and reduce the amount of time that exudate waspresent at the site of injury. When evaluated for time to completeclosure of the wound, application of the Test Article was found toaccelerate healing. Wounds treated with the test article achievedcomplete closure by Day 7-10 post injury, whereas wounds treated withthe standard of care required 10-14 days. At 7 days, wounds treated withthe positive control article appeared to be healing at the same rate aswounds treated with the Test Article. By Day 10, three of these woundshad reopened suggesting that wounds treated with the Test Article hadbetter durability of closure. This effect is mirrored in the evaluationof wound area. Application of the Test Article daily to the wounds wasfound to substantially reduce the size of the wound over time. Uponmicroscopic evaluation, a slight decrease was noted in subacuteinflammation, the degree of neovascularization, and granulomatousinflammation in the Test Article treated wounds. The results of thisstudy demonstrate that application of the Test Article providesaccelerated healing with reduced localized erythema and inflammation.

Example 2: Irritation as Measured by the Method of Lanman et al.

The Lanman et al. method of irritation measurement was conducted with avehicle cream (“Test Cream”). The objective of this study was to comparethe relative cumulative irritation potential of topically applied creamto a negative (Johnson's® Baby Oil) and a positive (0.2% v/v SodiumLauryl Sulfate) control following repetitive daily applications to theskin of normal healthy, adult volunteers. This was a single center, testsite randomized, clinical trial designed to evaluate the relativecumulative irritation potential of these test articles. The compositionsused were the Test Cream, Johnson's® Baby Oil and 0.2% Sodium LaurylSulfate (v/v in DI water). These were rubbed in to the upper backbetween the left and right infra-scapular areas and then covered with ablank semi-occlusive patch. Application sites were randomized as totheir position on the subjects' backs to eliminate test site bias.Products were rubbed in and blank semi-occlusive patches were applied tothe same sites every day for twenty-one (21) consecutive days for atotal of 21 applications. Each patch was worn for approximately 24hours, removed under clinical supervision and the test sites evaluatedapproximately 10 minutes following patch removal. Briefly, undersemi-occlusive conditions and for up to 21 days, the data revealed thatTest Cream was very well tolerated (non-irritating) and its tolerabilitywas comparable to Johnson's Baby Oil (Negative Control).

Example 3: Sensitization

The ISO 10993-10: 2002 method was used to evaluate the allergenicpotential or sensitizing capacity of a vehicle foam formulation (“TestFoam”), by screening of contact allergens in guinea pigs andextrapolating the results to humans. In the Induction Phase, ten testguinea pigs were patched with the Test Foam and 5 guinea pigs werepatched with the negative control article, removed after at least 6 hourexposure. After a 24-hour rest period, each site was observed forerythema and edema. The procedure was repeated 3 times per week for 3weeks. In the Challenge Phase, following a 2 week rest period, theanimals were topically patched again, removed after at least 6 hours ofexposure. Dermal patch sites were observed for erythema and edema 24 and48 hours after patch removal. Each animal was assessed for asensitization response and test results were based upon incidence andseverity of the sensitization reaction.

None of the animals showed abnormal clinical signs during the testperiod. There was no irritation observed on the Test Foam and controlanimals during the induction phase. The dermal response incidence was0%. None of the test animals challenged with the Test Foam was observedwith a sensitization response at any time point, indicating a 0%incidence. The severity was calculated as 0 at each time point. Theincidence of dermal response to repeat patch sensitization testing forthe Test Foam was zero in the study demonstrating that the Test Foamdoes not cause dermal sensitization.

Example 4: Comedogenicity

Using the method for measuring comedogenicity detailed above, a vehiclecomposition and a negative control produced significantly lessmicrocomedones than a positive control (P=0.003 and P=0.037,respectively) and the number of microcomedones at the sites treated withthe composition was not significantly different from the number ofmicrocomedones observed at the negative control sites.

Example 5: Antibacterial Effect (e.g., of Vehicle)

Twenty subjects were evaluated, ten subjects per each of the challengespecies. Upon completion of a 7-day product restriction period, atrained technician applied the test formulation to the skin of onerandomly assigned forearm. The subjects' other forearms served asuntreated controls and received no test formulation. Four sites weredelineated on the skin of each forearm and, 10 minutes following theproduct application procedure, the sites were exposed to the randomlyassigned challenge suspension for contact times of 5 minutes, 10minutes, 20 minutes, and 40 minutes and then sampled. Contaminated siteswere not occluded, but subjects were sequestered for the duration of theevaluation.

The 7 days prior to the test portion of the study constituted thepre-test period. During this time, subjects avoided the use of medicatedsoaps, lotions, deodorants and shampoos, as well as skin contact withsolvents, detergents, acids and bases, or any other products known toaffect the normal microbial populations of the skin. Subjects weresupplied a personal hygiene kit containing non-medicated soap, shampoo,lotion, and rubber gloves to be worn when contact with antimicrobials,solvents, detergents, acids, or bases cannot be avoided. Subjects wereinstructed to use the contents of this kit exclusively during theirparticipation in the study. Subjects also avoided using UV tanning bedsor sunbathing, and swimming or bathing in biocide-treated pools or hottubs.

Escherichia coli (ATCC #11229) and Staphylococcus aureus aureus MRSA(ATCC #33593) were used to challenge the efficacy of the testformulation.

Approximately 48 hours prior to initiating the study, sterile tubes ofTryptic Soy Broth (TSB) were inoculated from cryogenic stock cultures orlyophilized vials containing E. coli and Staph. aureus MRSA. Themicroorganism cultures were incubated at 30°±2° C. for approximately 24hours. Approximately 24 hours prior to initiating the study, the brothcultures were inoculated onto the surface of Tryptic Soy Agar (TSA) andincubated at 30°±2° C. for approximately 24 hours Immediately prior toinitiating the test procedure, suspensions of bacteria were prepared bytransferring growth from the cultures on TSA into test tubes containingsterile Phosphate Buffer Solution (PBS). Suspension concentrations ofapproximately 1.0×10⁹ CFU/mL were prepared, determined on the basis ofturbidity. Serial dilutions of the challenge suspension were made in PBSto achieve a final challenge inoculum of approximately 1.0×107 CFU/mL.The final challenge inoculum was assayed for number of organisms at thebeginning and at the end of the use period.

The left or right forearm was randomized to treatment with the testformulation, and the remaining forearm served as the untreated control.Following demarcation (see below), the four test sites on the skin ofeach forearm were assigned randomly and bilaterally to post-treatmentsample times. Prior to sampling, the subjects were questioned regardingadherence to the protocol. Subjects were examined physically to ensureno evidence of injury was present on the skin of the forearms. The skinof the forearms was rinsed with 70% isopropyl alcohol (IPA) and allowedto air-dry. A technician selected and marked with an indelible inkmarker four test sites on the volar surface of each forearm within a 2inch by 7 inch area. The sites were spaced uniformly, startingsequentially (one through four) from the elbow moving distally towardthe wrist, and the ink was allowed to dry thoroughly before continuing.1.0 mL of the test formulation was then applied to all four sites on therandomly-assigned forearm and a gloved hand was used to distribute theproduct evenly over all test sites. Any test formulation that dripped tothe underside of the arm was wiped with a paper towel. The test sites onforearms assigned as untreated control were not treated with testformulation.

10 minutes±1 minute following application of test formulation (orfollowing the initial decontamination of the untreated control), thefour test sites were exposed to 10 microliter of the challengesuspension of E. coli or Staph. aureus MRSA. Following 40 minute±1minute exposure, 20 minute±1 minute exposure, 10 minute±1 minuteexposure, and 5 minute±1 minute exposures, individual sites were sampledusing the Cylinder Sampling Technique and then decontaminated with 70%IPA.

The cylinder sampling technique was performed as follows:

At the designated time, a sterile cylinder with an inside area of 3.46cm2 was held firmly onto the test site to be sampled. 2.5 mL of sterileStripping Suspending Fluid with appropriate product neutralizers (SSF++)was instilled into the cylinder, and the skin area inside the cylindermassaged in a circumferential manner for 1 minute with a sterile rubberpoliceman.

The 2.5 mL of SSF++ was removed with a pipette and transferred to asterile test tube. A second 2.5 mL aliquot of SSF++ was instilled intothe cylinder, and the skin area again massaged for 1 minute with arubber policeman.

The second 2.5 mL aliquot was pooled in the test tube with the firstaliquot.

Subjects were not allowed to leave the laboratory for any reason oncethe testing began. Additionally, subjects were required to wearprotective garments and not touch their clothing, faces, or any otherbody parts with their forearms during the test period. On completion oftesting, subjects were required to perform a I-minute rinse of theirforearms with 70% ethanol and an air dry, followed by a supervised4-minute wash with a 4% chlorhexidine gluconate solution. A topicalantibiotic ointment was applied to the forearms following thedecontamination procedure.

Duplicate spiral plates or duplicate spread plates were prepared fromcylinder samples (10° dilution) on MacConkey Agar (MAC) for Escherichiacoli (ATCC #11229) and Hardy Chrom Staph aureus (CHROM) forStaphylococcus aureus aureus MRSA strain (ATCC #33593). These wereincubated at 30°±2° C. for approximately 48 hours and at 35°±2° C. forapproximately 24 hours, respectively, or until sufficient growth wasobserved. Colonies were counted and data recorded using the Q-Countplate counting system or equivalent.

Example 6: Tinea

This study is a multi-center, evaluator-blinded, randomized, vehiclecontrolled, parallel group comparison of Econazole Nitrate Foam 1%(according to Table B) with Econazole Nitrate Cream 1% (Fougera®, AltanaInc.) and the Foam vehicle.

The study enrolls subjects presenting with a clinical diagnosis of tineapedis (Interdigital and/or Moccasin-type) and a positive KOH finding atthe Screening/Baseline visit. Subjects who meet the inclusion/exclusioncriteria are randomized (1:1:1) to treatment with Econazole Nitrate Foam1%, Foam Vehicle, or Econazole Nitrate Cream 1%. Blood is drawn toobtain baseline labs (chemistry, hematology, and urinalysis) and abaseline drug plasma level (selected sites only). The assigned studymedication is applied once daily preferably in the mornings for 4 weeks.Given the physical differences in the two “active” dosage forms (foamand cream), particular care is taken to assure the clinical evaluator is“blinded” with respect to the medication type dispensed to the subjects.

At Days 8 and 15, a safety evaluation and clinical grading is performed.Dermatophyte cultures taken at the Baseline visit are reviewed to ensurethat subjects are eligible to continue in the study. Subjects withnegative Baseline dermatophyte cultures, exclusive of subjectsparticipating in the pharmacokinetic aspect of the trial, arediscontinued from the study. If fungal culture results are pending atany visit, the subjects continued treatment until the next visit.

At the end-of-treatment (Day 29) a safety evaluation, clinical gradingand repeat KOH test and mycological culture are performed. All subjectsare asked to withhold the last morning application of the studymedication until after skin scrapings (specimens for KOH and cultures)has been collected. At this visit, all subjects had blood drawn toobtain end-of-treatment (EOT) labs (chemistry, hematology, andurinalysis).

Blood is also drawn from all subjects at selected PK sites to obtainplasma drug levels on Day 29. Prior to this visit, subjects at PK sitesare asked to withhold application of the study medication until afterthe initial blood draw has been taken. Following this initial blooddraw, the subject applies the medication to the designated areas on thefeet (as per Section 6.2 of the protocol) and the time of applicationand the surface area of application is estimated. Subjects have bloodtaken at 1, 2, 4, 6, 8, and 12 hours post-application. Subjects withnegative Baseline fungal cultures are discontinued at this visit.

For subjects at the PK sites, body surface area (BSA) is calculated fromheight and weight measurements using the Mosteller formula: BSA(m2)=square root ((Height, inches×Weight, pounds)/3131). Total surfacearea (TSA in cm2) treated with the study medication is derived using thefollowing formula: TSA (cm2)=0.07*10,000*BSA (m2). Subjects shoe size isrecorded on the Case Report Forms (CRFs) but is not used to calculatetotal surface area of the feet. The surface area of the treatment areais calculated from the Mosteller formula using the assumption that thesurface area of both feet is 7% of the total body surface area.

At the end of study (Day 43), subjects with positive Baseline fungalcultures return for the final visit for clinical evaluations and repeatKOH testing and mycological cultures are performed.

The statistical analysis and study endpoints are detailed in a protocoland included clinical as well as mycology outcome measures. At eachvisit, adverse reactions including local skin reactions, concurrentprocedures, and changes in concomitant medications during the study arerecorded.

Subjects who do not participate in any pharmacokinetic portion of aprotocol are instructed to treat the entire sole/sides and interdigitalarea of both feet, independent of what form (Moccasin and/orInterdigital) of tinea pedis the subject had. Subjects are instructed toapply a thin uniform coat of study medication over the entire sole ofthe foot extending onto the sides of the foot for about 2.5 cm (1 inch)beyond the affected skin. Subjects participating in any pharmacokineticpart of the protocol are instructed to treat both feet by applying athin uniform coat of the study medication over each foot in its entiretyup to the inferior aspect of their ankles once a day (i.e., soles, toes,interdigital spaces and the top surfaces of both feet up to the ankles)independent of the area of disease involvement.

Intent-to-Treat Population: All subjects enrolled in the study that arerandomized, and dispensed study medication are considered in the ITTpopulation. Subjects who discontinue prematurely from the studyfollowing administration of study medication (e.g., subjects who arefound to lack a positive baseline fungal culture) are included in theITT population. No efficacy analyses are conducted on the ITTpopulation.

Modified Intent-to-Treat (“MITT”) Population: All subjects enrolled inthe study who are randomized and dispensed study medication, and whohave a positive baseline fungal culture are included in the MITTpopulation, a subset of the ITT population.

Per-Protocol (“PP”) Population: Subjects are included in the PP efficacyanalyses if they are dispensed and apply the study medication and meetall of the following conditions:

Positive Baseline KOH evaluation and positive fungal culture;

Week 6, Visit 5, is within protocol-specified windows: Day 43±4 days;

Receive drug as randomized;

Minimum number of doses received is defined as 80% of doses based onstart and stop dates of study medication application;

Blinded clinical review finds no significant violations of eligibilitycriteria including no use of prohibited medications/therapies during thestudy.

Endpoints can be (e.g., two weeks after end-of-treatment:

Complete cure (negative KOH, negative culture, and no evidence ofclinical disease as indicated by scores of 0 for each sign and symptom(erythema, scaling/hyperkeratosis, cracking/fissuring, maceration,vesiculation, and pruritus) at Day 43);

Effective treatment (negative KOH, negative culture, no or mild erythemaand/or scaling/hyperkeratosis (score of 0 or 1) with all other signs andsymptoms being absent (score=0) at Day 43);

Mycological cure (negative KOH and negative fungal culture at Day 43).

Efficacy Results

Similar cure rates and safety profiles between the test drug (EconazoleNitrate Foam) and reference product (Econazole Nitrate Cream) suggestthat they were comparable and both were significantly better compared tovehicle. Complete cure rates in both active formulation groups werestatistically significantly higher than those in the Foam Vehicle groupin the MITT and PP populations (p<0.01, Econazole Nitrate Foam vs. FoamVehicle; p<0.05, Econazole Nitrate Cream vs. Foam Vehicle). Effectivetreatment and Mycological cure rates with both active formulations werestatistically significantly superior (p<0.0001) to those in the FoamVehicle groups in the MITT and PP populations. Consistent with thesefindings, changes in signs and symptoms from Baseline to TOC (Day 43)indicate that both econazole formulations were effective in reducing theseverity of signs and symptoms of Interdigital TP and Moccasin TP.

Safety Results

Both Econazole Nitrate Foam 1% and Econazole Nitrate Cream 1% were welltolerated with no reports of serious adverse events and nodiscontinuations from the study due to adverse events. There were nosignificant differences in the safety profiles of subjects across thethree treatment groups. The number of subjects who experienced adverseevents was comparable across each of the three treatment groups. Most ofthese adverse events were mild or moderate in severity and not relatedto study medication. Pharmacokinetic analysis of plasma levels ofeconazole following the last application of study medicationdemonstrated that the extent of systemic exposure to econazole followingEconazole Nitrate Foam 1% was not statistically significantly differentfrom the exposure following Econazole Nitrate Cream 1%.

Publications and references, including but not limited to patents andpatent applications, cited in this specification are herein incorporatedby reference in their entirety in the entire portion cited as if eachindividual publication or reference were specifically and individuallyindicated to be incorporated by reference herein as being fully setforth. Any patent application to which this application claims priorityis also incorporated by reference herein in the manner described abovefor publications and references.

While this invention has been described with an emphasis upon preferredembodiments, it will be obvious to those of ordinary skill in the artthat variations in the preferred devices and methods may be used andthat it is intended that the invention may be practiced otherwise thanas specifically described herein. Accordingly, this invention includesall modifications encompassed within the spirit and scope of theinvention as defined by the claims that follow.

What is claimed is:
 1. A method of treating an infection by dermatophytefungus comprising: applying to an infected skin area a water-based foamcomposition, wherein the foam remains stably adherent to the skin areafor at least 30 seconds following the applying, and, wherein thewater-based foam composition consists of: econazole or apharmaceutically acceptable salt thereof; 8.0-9.0 wt. % of one or moreC12-C22 fatty acids; 0.5-2.0 wt. % of an emollient selected from thegroup consisting of: a silicone oil, a petrolatum, and a combinationthereof; 3.0-4.0 wt. % of one of more emulsifying agents; 1.0-2.5 wt. %of one or more film-forming polymers; 6.0-9.0 wt. % of one or morehumectants selected from the group consisting of: glycerol and propyleneglycol; a titrating agent comprising triethanolamine in an amount of 1.0to 3.0% by weight of the water-based foam composition so that an amountof the fatty acid component is in the ionized form and a remaining partof the fatty acid component is in the non-ionized form; one or morepropellants; and water; wherein the composition has a pH of about 6-9.2. The method of claim 1, wherein the infection is tinea pedis, tineacruris, tinea corporis, or tinea versicolor.
 3. The method of claim 2,wherein the infection is tinea pedis.
 4. The method of claim 3, whereinthe infection is interdigital tinea pedis.
 5. The method of claim 1,further comprising shaking the water-based foam composition prior toapplication.
 6. The method of claim 1, wherein the water-based foamcomposition is essentially free of C1 to C6 alcohols, not includingpolyols.
 7. The method of claim 1, wherein the water-based foamcomposition is non-comedogenic.
 8. The method of claim 1, wherein thecomposition consists of, by weight % of the composition: stearic acid inan amount in the range of 2.0-8.0%; polyvinyl pyrrolidone in an amountin the range of 1.0-5.0%; econazole nitrate in an amount in the range of0.5-1.5%; propylene glycol in an amount in the range of 4.0-8.0%;glycerin in an amount in the range of 1.0-5.0%; dimethicone in an amountin the range of 0.5-5.0%; triethanolamine in an amount in the range of2.0-3.0%; and polysorbate 20 in an amount in the range of 1.0-4.0%.
 9. Amethod of treating an infection by dermatophyte fungus comprising:applying to an infected skin area a water-based foam composition,wherein the water-based foam composition consists of: econazole or apharmaceutically acceptable salt thereof; 8.0-9.0 wt. % of one or morefatty acids, the fatty acid having an ionized form and a non-ionizedform, and selected such that 75 mole % or more is C12-C22 fatty acid;3.0-4.5 wt. % of one or more emulsifying agents; 1.5-2.5 wt. % of one ormore film-forming polymers; 0.5-1.5 wt. % of one or more emollients;7.0-8.0 wt. % of one or more humectants; a titrating agent comprisingtriethanolamine in an amount of 2.0 to 3.0% by weight of the water-basedfoam composition so that an amount of the fatty acid component is in theionized form and a remaining part of the fatty acid component is in thenon-ionized form; one or more propellants; and water; wherein thecomposition has a pH of about 6-9.
 10. The method of claim 9, whereinthe composition consists of: stearic acid, polyvinyl pyrrolidone,econazole nitrate, propylene glycol, glycerin, dimethicone,triethanolamine, polysorbate 20, one or more propellants, and water. 11.The method of claim 10, wherein a propellant is propane, butane,isobutene, another hydrocarbon, hydrofluorocarbon, or achlorofluorocarbon.
 12. The method of claim 1, wherein the water-basedfoam composition consists of: 0.5-1.5 wt. % of econazole nitrate;8.0-9.0 wt. % of stearic acid substantially in an ionized form; 1.0-2.5wt. % of povidone 6-9 wt. % of one or more humectants, the one or morehumectants being one or both of propylene glycol and glycerol; 0.5-2 wt.% of dimethicone 2.0-3.0 wt. % of triethanolamine 3.0-4.0 wt. % ofpolysorbate 20; water; and one or more propellants; wherein thecomposition has a pH in the range of about 6-9; and wherein the weight %of the above ingredients are provided exclusive of the one or morepropellants present in the composition.
 13. The method of claim 12,wherein the water-based foam composition consists of: 1.0 wt. %econazole nitrate; 8.0 wt. % of stearic acid; 1.9-2.5 wt. % of povidone5.8 wt. % of propylene glycol 1.7 wt. % of glycerol; 0.95 wt. % ofdimethicone 2.6 wt. % of triethanolamine 3.7 wt. % of polysorbate 20;water; and one or more propellants.
 14. A foamable composition,consisting of: 2-8 percent by weight of stearic acid; 1-5 percent byweight of polyvinylpyrrolidone; 0.5-1.5 percent by weight econazole or apharmaceutically acceptable salt thereof; 4-8 percent by weight ofpropylene glycol; 1-5 percent by weight of glycerin; 0.5-5 percent byweight of dimethicone; 2-3 percent by weight of triethanolamine; 1-4percent by weight of polysorbate 20; one or more propellants; and water:wherein the composition has a pH of about 6-9; and wherein an amount ofthe fatty acid component is in the ionized form and a remaining part ofthe fatty acid component is in the non-ionized form.
 15. The compositionof claim 14, packaged in a dispensing device.